The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission.
The neurodegenerative disorder spinocerebellar ataxia 12 (SCA12) is caused by CAG repeat expansion in the non-coding region of the PPP2R2B gene. PPP2R2B encodes Bbeta1 and Bbeta2, alternatively spliced and neuron-specific regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme. We show here that in PC12 cells and hippocampal neurons, cell stressors induced a rapid translocation of PP2A/Bbeta2 to mitochondria to promote apoptosis. Conversely, silencing of PP2A/Bbeta2 protected hippocampal neurons against free radical-mediated, excitotoxic, and ischemic insults. Evidence is accumulating that the mitochondrial fission/fusion equilibrium is an important determinant of cell survival. Accordingly, we found that Bbeta2 expression induces mitochondrial fragmentation, whereas Bbeta2 silencing or inhibition resulted in mitochondrial elongation. Based on epistasis experiments involving Bcl2 and core components of the mitochondrial fission machinery (Fis1 and dynamin-related protein 1), mitochondrial fragmentation occurs upstream of apoptosis and is both necessary and sufficient for hippocampal neuron death. Our data provide the first example of a proapoptotic phosphatase that predisposes to neuronal death by promoting mitochondrial division and point to a possible imbalance of the mitochondrial morphogenetic equilibrium in the pathogenesis of SCA12.
Dagda
Ruben K
RK
Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242, USA.
Merrill
Ronald A
RA
Cribbs
J Thomas
JT
Chen
Yucui
Y
Hell
Johannes W
JW
Usachev
Yuriy M
YM
Strack
Stefan
S
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D002470:Cell Survival; D004843:Epistasis, Genetic; D006624:Hippocampus / Q000378:metabolism; D007511:Ischemia; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D012313:RNA / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D020754:Spinocerebellar Ataxias / Q000235:genetics*
D002352:Carrier Proteins; C538792:PPP2R2B protein, rat; D012402:Rotenone; D012313:RNA; D054648:Protein Phosphatase 2